Cancer is the second leading cause of death after heart disease and is the primary cause of death in women between the ages of 35 and 74 in the United States. Based on estimates of the National Institutes of Health, overall costs for cancer in the year 2000 were 180.2 billion U.S. dollars. Cancer-related costs account for about 10 percent of the total amount spent on disease treatment in the United States. Thus, cancer is a major national burden.
Breast cancer is the most common cancer among American women, except for skin cancers. In addition, breast cancer is the second leading cause of cancer death in women, exceeded only by lung cancer. The chance of developing invasive breast cancer at some time in a woman's life is about 1 in 8 (12%). Women living in North America have the highest rate of breast cancer in the world and it is estimated that about 178,480 new cases of invasive breast cancer will be diagnosed among women in the United States in 2007.
Recent studies have led to the identification of classes, or sub-types, of breast cancer that are defined by gene expression profiles and molecular features (Lønning et al., Endocrine-Related Cancer 8:259-263 (2001)). These include Luminal A, Luminal B, HER2-type, normal breast-like and basal-like breast cancers. Basal-like breast cancers are high-grade cancers that are associated with rapid growth and poor prognosis, including high risk for metastasis, recurrence, and death. There is no definitive test or validated clinical assay at this time that accurately identifies basal-like breast cancers. Accordingly, there is an urgent need to identify new markers that can be used to recognize basal-like breast cancer more readily and to develop targeted treatments for this disease.
Human TTK protein kinase (TTK), also known as tyrosine threonine kinase, dual specificity protein kinase TTK, Monopolar Spindle 1 (Mps1) and Phosphotyrosine-Picked Threonine Kinase (PYT), is a conserved multispecific kinase that is capable of phosphorylating serine, threonine and tyrosine residues when expressed in E. coli (Mills et al., J. Biol. Chem. 22(5): 16000-16006 (1992)). TTK mRNA is not expressed in the majority of physiologically normal tissues in human (Id). TTK mRNA is expressed in some rapidly proliferating tissues, such as testis and thymus, as well as in some tumors (TTK mRNA was not expressed in renal cell carcinoma, was expressed in 50% of breast cancer samples, was expressed in testicular tumors and ovarian cancer samples) (Id). TTK is expressed in some cancer cell lines and tumors relative to normal counterparts (Id.; see also WO 02/068444 A1).
The yeast homolog of human TTK, Mps1, is required for normal cell cycle progression and has been shown to have a role in centrosome/spindle body duplication, the mitotic spindle checkpoint and cytokinesis (Winey and Huneycutt, Oncogene 21: 6161-6169 (2002)). Studies in Drosophila and vertebrates have confirmed that several of these functions are conserved in higher eukaryotes, including humans (Fisk and Winey, Curr. Biol. 14: R1058-1060 (2004); Fischer et al., Curr. Biol. 14: 2019-2024 (2004); Fisk et al., PNAS 100(25): 14875-14880 (2003)). The specific biochemical role of TTK in cellular physiology is not currently understood.
The requirement of normal TTK kinase activity for controlled cell cycle progression in yeast, Drosophila, and vertebrates, including humans, combined with the detection of TTK overexpression in some human cancer samples and cancer cell lines indicates that TTK should be investigated further as a potential target for therapeutic anti-cancer agents. However, the role of TTK in the pathology of breast cancer and particular subtypes of breast cancer is not understood.
There is a need to determine whether TTK expression and/or activity is associated with particular subtypes of breast cancer. In addition, there is a need to identify and develop therapeutic agents that target TTK expression and/or activity to treat breast cancer subtypes that are characterized by TTK overexpression.